55837-20-2

Basic information

• Product Name: Halofuginone
• Synonyms: 7-Bromo-6-chloro-3[3-(3-hydroxy-2-piperidi-nyl)-2-oxopropyl]-4(3H)-quinzolinone;trans-7-bromo-6-chloro-3-(3-(3-hydroxy-2-piperidinyl)-2-oxopropyl)-4(3h)-qui;trans-l);7-Bromo-6-chloro-3-(3-(3-hydroxypiperidin-2-yl)-2-oxopropyl)quinazolin-4(3H)-one;7-Bromo-6-chlorofebrifugine Hydrochloride;Halofuginone Hydrochloride;rel-7-Bromo-6-chloro-3-[3-[(2R,3S)-3-hydroxy-2-piperidinyl]-2-oxopropyl]-4(3H)-quinazolinone Hydrochloride;HALOQUGINONE
• CAS NO: 55837-20-2
• Molecular Formula: C16H17BrClN3O3
• Molecular Weight: 414.68
• EINECS: 1806241-263-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 55837-20-2.mol

Chemical Properties

• Melting Point: >150°C dec.
• Boiling Point: 595.8 °C at 760 mmHg
• Flash Point: 314.1 °C
• Appearance: off-white solid
• Density: 1.73 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.712
• Storage Temp.: -20°C
• PKA: 14.61±0.40(Predicted)
• CAS DataBase Reference: Halofuginone(CAS DataBase Reference)
• NIST Chemistry Reference: Halofuginone(55837-20-2)
• EPA Substance Registry System: Halofuginone(55837-20-2)

Safety Data

• Hazardous Substances Data: 55837-20-2(Hazardous Substances Data)

Usage

Uses

Used in Antiprotozoal Applications:
Halofuginone is used as an antiprotozoal agent, particularly for the treatment or prevention of coccidiosis in both humans and animals.
Used in Poultry Industry:
Halofuginone is used as a coccidiostat for young chickens and young turkeys, helping to prevent and control coccidiosis, a parasitic disease that affects these birds. However, it is important to note that in higher doses, halofuginone can act as a growth depressant, impair feed utilization, and reduce feed intake. Additionally, it is prohibited from use during the last four days before slaughter (withdrawal period) to ensure that the compound is not present in the final product.
Chemical Extraction and Analysis:
Halofuginone is extracted from enzyme-digested chicken liver as a free base into ethyl acetate and then partitioned into ammonium acetate buffer solution. Halofuginone is concentrated using Sep-Pak C18 cartridges and eluted with methyl alcohol. The eluant is evaporated to dryness, and the residue is dissolved in the HPLC mobile phase. Analysis of halofuginone is achieved by high-performance liquid chromatography (HPLC) using a BONDAPAK C18 column and a variable wavelength UV detector.

Biological Activity

Halofuginone is a halogenated derivative of febrifugine, a natural quinazolinone-containing compound found in the Chinese herb D. febrifuga. It has antimalarial and anticoccidial actions. In mammals, halofuginone at 10 ng/ml down-regulates Smad3, blocking TGF-β signaling and preventing both the differentiation of fibroblasts to myofibroblasts and the transitioning of epithelial cells to mesenchymal cells. Through this action, halofuginone blocks fibrosis and tumor progression in a variety of different models. Halofuginone also competitively inhibits prolyl-tRNA synthetase (Ki = 18.3 nM), activating the amino acid starvation response. This prevents the differentiation of TH17 cells, blunting an autoimmune response.

Synthesis

A scalable total synthesis of halofuginone has been accomplished. This synthetic route features a total of 12 steps of highly efficient reactions, without any chromatographic purification. Halofuginone was obtained in 17% overall yield and over 98.5% HPLC purity. All the reaction conditions are mild and reliable. In addition, no hazardous materials are used or produced. All reagents are commercially available and inexpensive. This route is safe, robust, scalable, cost-effective, and environmentally benign.A Scalable Total Synthesis of Halofuginone

Mode of action

Halofuginone is an analog of febrifugine-an alkaloid originally isolated from the plant Dichroa febrifuga. During recent years, halofuginone has attracted much attention because of its wide range of beneficial biological activities, which encompass malaria, cancer, and fibrosis-related and autoimmune diseases. At present two modes of halofuginone actions have been described: (1) Inhibition of Smad3 phosphorylation downstream of the TGFβ signaling pathway results in inhibition of fibroblasts-to-myofibroblasts transition and fibrosis. (2) Inhibition of prolyl-tRNA synthetase (ProRS) activity in the blood stage of malaria and inhibition of Th17 cell differentiation thereby inhibiting inflammation and the autoimmune reaction by activation of the amino acid starvation and integrated stress responses.

InChI:InChI=1/C16H17BrClN3O3/c17-11-6-13-10(5-12(11)18)16(24)21(8-20-13)7-9(22)4-14-15(23)2-1-3-19-14/h5-6,8,14-15,19,23H,1-4,7H2/t14-,15+/m1/s1

Upstream product

• 1203455-38-2 (2S,3R)-3-benzyloxy-2-[2-oxo-3-(7-bromo-6-chloro-4-oxoquinazolin-3(4H)-yl)propyl]piperidine-1-carboxylic acid benzyl ester 
• 1203455-28-0 (2R,3S)-3-benzyloxy-2-[2-oxo-3-(7-bromo-6-chloro-4-oxoquinazolin-3(4H)-yl)propyl]piperidine-1-carboxylic acid benzyl ester 
• 17518-98-8 7-bromo-6-chloro-3,4-dihydroquinazolin-4-one 

Downstream Products

• 17395-31-2 halofuginone hydrobromide 
• 82186-71-8 (rac)-halofuginone lactate 
• 17395-31-2 halofuginone hydrobromide 

Relevant articles and documents

A Scalable Total Synthesis of Halofuginone

A scalable total synthesis of halofuginone has been accomplished. This synthetic route features a total of 12 steps of highly efficient reactions, without any chromatographic purification. Halofuginone was obtained in 17% overall yield and over 98.5% HPLC purity. All the reaction conditions are mild and reliable. In addition, no hazardous materials are used or produced. All reagents are commercially available and inexpensive. This route is safe, robust, scalable, cost-effective, and environmentally benign.

(2R,3S)-(+)- and (2S,3R)-(-)-Halofuginone lactate: Synthesis, absolute configuration, and activity against Cryptosporidium parvum

The trans-enantiomers of the commercially important anti-protozoal compound Halofuginone have been prepared and characterized, and the absolute configuration was assigned by X-ray crystallography. The activity of both enantiomers against Cryptosporidium parvum was determined in vitro and related to acute toxicity in vivo. It was shown that both the activity and the toxicity are properties of the (2R,3S)-enantiomer. We conclude that with respect to broadening the therapeutic window there is no advantage in application of one enantiomer over the application of the racemic mixture in the treatment of C. parvum infections.

New synthesis process for preparing veterinary bulk drug halofuginone hydrobromide

The invention discloses a process method for preparing veterinary raw material drug halofuginone hydrobromide, and relates to the field of veterinary drugs and the technical field of drug synthesis. According to the invention, a novel process route is adopted, 7-bromo-3-(8-bromo-5-hydroxy-2-oxo-3-octenyl)-6-chloro-4 (3H)-quinazolinone is taken as a starting raw material, and the halofuginone hydrobromide is prepared through three-step reaction of ammonolysis, purification and salification, so that the problems of difficulty in obtaining raw materials, harsh reaction conditions, high cost and the like in the existing synthesis method are solved. The novel synthesis process for preparing the veterinary drug halofuginone hydrobromide is simple in process operation, low in production cost, few in steps, high in total yield, small in pollution and suitable for industrial mass production.

Halofuginone with optical activity and synthesis method of intermediate of halofuginone

The invention relates to a preparation method of cis-2-(2-chloropropene)-3-hydroxyl piperidine with optical activity and application of cis-2-(2-chloropropene)-3-hydroxyl piperidine in preparing halofuginone. The preparation method of cis-2-(2-chloropropene)-3-hydroxyl piperidine with optical activity comprises the following steps: (1) in a first organic solvent, performing a salt forming reactionon racemic cis-2-(2-chloropropene)-3-hydroxypiperidine and dibenzoyltartaric acid or a derivative thereof so as to generate precipitate, recrystallizing the precipitate so as to obtain a chiral composite salt; and (2) in a second organic solvent, neutralizing the chiral composite salt to alkaline by using an alkali water solution, so as to obtain the cis-2-(2-chloropropene)-3-hydroxyl piperidinewith optical activity. The method is cheap in raw material, easy in raw material obtaining, simple in preparation process, small in product impurity and free of column chromatography purification, andin addition, on-scale production preparation of halofuginone with a high optical purity can be achieved.

Synthetic method for halofuginone and intermediate of halofuginone

The invention relates to a synthetic method for halofuginone and an intermediate of the halofuginone. The reaction formula is shown in the description, wherein R1 is one selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and t-butyl; R2 is one selected from the group consisting of methyl and ethyl; and R3 is one selected from the group consisting of methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl and benzyl. The synthetic method provided by the invention has the advantages of a simple process, low costs, few by-products in the synthetic process, a simple purification process, no need of column chromatography purification, a high product yield, less impurities, high purity, and controllable product quality, easily meets ICH declaration requirements and can be used for industrial production of the halofuginone.

An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers

A new synthesis of both enantiomers of naturally occurring febrifugine (1) and its analogue halofuginone (3) are reported. This robust route relies on an enzymatic kinetic resolution (EKR)-cross metathesis (CM) sequence, performed on allylic alcohol 8. A diastereoselective Lewis acid-mediated cyclisation of resultant enone 6 affords piperidine 12. In relation to its enantiomeric excess, values of 87 and 88% e.e were obtained for both enantiomers of 12 and for (?)-12 this was increased to 98% e.e by conducting the resolution process twice. A bromination (featuring an in situ temporary alcohol protection), alkylation and amino-deprotection sequence finally afforded the target compounds (+)- and (?)-1, and (+)- and (?)-3. Studies demonstrate that, as their ammonium salts, the compounds are stereochemically stable. However, as their free-bases, particularly in chloroform, C-2 isomerisation occurs. This isomerisation has been taken advantage of synthetically to provide enantioenriched (+)-isofebrifugine (2) and both enantiomers of isohalofuginone (14).

A novel synthesis of the efficient anti-coccidial drug halofuginone hydrobromide

Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and 1H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.

METHOD FOR PREPARING HALOFUGINONE DERIVATIVE

A method for preparing a halofuginone derivative, in particular a method for preparing an inhibitor medicament expressed by specific I-type procollagen in the invention a condensate of formula (II) reacts for 12-35 hours in a catalytic hydrogenation solvent with the existence of Ni—B amorphous alloy catalyst, at the hydrogen pressure of 0.1-10 Mpa and at the temperature of 10-60° C., and then the catalyst is filtered, the filtrate is decompressed to recover the solvent, the pH value is regulated to obtain a crude product of formula (I), and the crude product of the formula (I) is refined to obtain a refined product of formula (I).

Dihydroxylation of vinyl sulfones: Stereoselective synthesis of (+)- and (-)-febrifugine and halofuginone

(Chemical Equation Presented) The asymmetric dihydroxylation of amino-functionalized vinyl sulfone 19 has been used for the 3-step preparation of 3-hydroxylpiperidine 24 in 86% enantiomeric excess. This enantiomerically enriched building block was used then to synthesize the naturally occurring antimalarial alkaloid febrifugine 1 and its antiangiogenic analogue, halofuginone 3.

Process for formulating a synthetic drug for use in animal feed, and resulting formulation

A method of formulating a synthetic drug for use in animal feed, for the purpose of reducing carry-over of the synthetic drug to subsequent lots of animal feed in the feed mill.